5-Pyrimidinecarboxamides, and particularly 5-carboxamides of barbituric acid, have previously been described as potential anti-cancer agents. Thus, Takeda Pharmaceutical Industries' Japanese Patent Publication No. 1,445/64, published on Feb. 14, 1964, suggests the use of compounds of the formula: ##STR2## i.e., 5-phenylcarbamoylbarbituric acid (wherein R is hydrogen) and 1-substituted-phenylcarbamoylbarbituric acids (wherein R is alkyl or phenyl), for such purpose. When subjected to in vivo testing on Ehrlich Ascites carcinoma in mice the unsubstituted compound, but neither its 1-methyl nor 1-phenyl-substituted derivatives, exhibited anti-tumor activity. Chem & Pharm. Bull. (Tokyo) 8, 1021-1028 (1960).
Other 5-carboxamido-substituted barbituric acids such as: ##STR3## wherein X is oxygen or sulfur; R.sub.1 and R.sub.2 may each be alkyl, alkenyl, benzyl or unsubstituted or substituted phenyl; R.sub.3 may be halogen, nitro or trihalomethyl; R.sub.4 is hydrogen, halogen or trihalomethyl; and R.sub.5 is hydrogen, halogen, methyl or methoxy, are also described in the patent literature. Such compounds are disclosed in Ciba-Geigy European Patent Publication No. 74,335 and in De Sousa et al., U.S. Pat. No. 4,283,444 granted on Aug. 11, 1981, as useful for protecting keratinous material, especially wool, from insect attack.
Analogs of similar barbituric acid derivatives have also been described in the literature. Thus, N-substituted-2-amidocarbonylthiobarbituric acids of the formula: ##STR4## wherein R.sup.1 is alkyl, alkenyl, various substituted alkyl, alkenyl or carbonyl, or optionally substituted aryl or aralkyl; R.sup.2 and R.sup.3 each independently is alkyl, alkenyl, cycloalkyl, aryl, aralkyl or hydrogen, provided that not more than one of R.sup.2 and R.sup.3 is hydrogen; and X is oxygen or sulfur, are disclosed in Bayer AG German Offen. No. 24 05 732 and in Kramer et al., U.S. Pat. No. 3,961,061 granted on June 1, 1976. These thiobarbituric acid derivatives are described as possessing insecticidal, acaricidal, fungicidal and bactericidal properties.
More recently, it has been disclosed in Brewer et al., U.S. Pat. No. 4,634,707, owned by the assignee of the present invention, the certain 5-carboxamido-2-thiobarbituric acid derivatives, viz., compounds of the formula: ##STR5## wherein R is hydrogen, 2 or 3-halo, 2-methyl, 4-fluoro, 4-(C.sub.1 -C.sub.6 alkoxyl), 2 or 4-trifluoromethyl, or hydroxyl, and R.sub.1 is hydrogen; or R is 2-fluoro and R.sub.1 is 4-fluoro; or R is 2-methoxy and R.sub.1 is 5-methyl; and R.sub.2 and R.sub.3 are hydrogen atoms or carbohydrate residues; and the pharmacologically acceptable addition salts thereof, induce regression or inhibit the growth of leukemia and various malignant tumors in mammals.
It is among the objects of the present invention to provide a new 5-pyrimidinecarboxamide which is a useful anti-leukemia and anti-tumor agent, as well as pharmaceutical compositions, and therapeutic methods for utilizing the same.
Other objects and advantages of the invention will be apparent from the following detailed description of preferred embodiments thereof.